Abstract
Limited studies have investigated population pharmacokinetic (PK) models and optimal dosage regimens of meropenem for critically ill adult patients using the probability of target attainment, including patients receiving extracorporeal membrane oxygenation (ECMO). A population PK analysis was conducted using non-linear mixed-effect modeling. Monte Carlo simulation was used to determine for how long the free drug concentration was above the minimum inhibitory concentration (MIC) at steady state conditions in patients with various degrees of renal function. Meropenem PK in critically ill patients was described using a two-compartment model, in which glomerular filtration rate was identified as a covariate for clearance. ECMO did not affect meropenem PK. The simulation results showed that the current meropenem dosing regimen would be sufficient for attaining 40%fT>MIC for Pseudomonas aeruginosa at MIC ≤ 4 mg/L. Prolonged infusion over 3 h or a high-dosage regimen of 2 g/8 h was needed for MIC > 2 mg/L or in patients with augmented renal clearance, for a target of 100%fT>MIC or 100%fT>4XMIC. Our study suggests that clinicians should consider prolonged infusion or a high-dosage regimen of meropenem, particularly when treating critically ill patients with augmented renal clearance or those infected with pathogens with decreased in vitro susceptibility, regardless of ECMO support.
Highlights
Antibiotic treatment is a major factor in determining the survival of critically ill patients diagnosed with sepsis
“third spacing” phenomenon caused by vasodilation and capillary leakage in sepsis patients increases the volume of distribution and lowers the drugs’ serum concentration, especially for hydrophilic antimicrobials [1,2], such as β-lactams and aminoglycoside, that are more affected by pathophysiological changes than lipophilic drugs [3]
PK of meropenem was bestilldescribed by patients, including those undergoing of meropenem was best described a two-compartment model, in which the glomerular filtration rate (GFR) was estimated byusing a two-compartment model, and in which the glomerular filtration rate (GFR)
Summary
Antibiotic treatment is a major factor in determining the survival of critically ill patients diagnosed with sepsis. Altered pharmacokinetics (PK) in these patients is a major obstacle for clinicians when determining an adequate antibiotic dosage regimen [1]. The “third spacing” phenomenon caused by vasodilation and capillary leakage in sepsis patients increases the volume of distribution and lowers the drugs’ serum concentration, especially for hydrophilic antimicrobials [1,2], such as β-lactams and aminoglycoside, that are more affected by pathophysiological changes than lipophilic drugs [3]. A carbapenem β-lactam agent with a wide spectrum of activity against
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